Dengue hemorrhagic fever (DHF) is the most common serious arboviral infection in the world, and is an emerging flavivirus infection, as is West Nile virus. The pathogenesis of DHF appears to be multi-factorial, but clearly involves host and viral factors, particularly pre-existing immune memory (antibodies and T lymphocytes) to dengue virus (DV). The goal of this Project is to define viral and immunological mechanisms that are responsible for DHF. The Project involves four Specific Aims addressing the hypothesis that DHF is induced by specific interactions between the innate and adaptive (memory) immune responses to DV infection: * Aim 1 focuses on the initial (afferent) stages of DV infection. We will study the formation of DV-antibody complexes in vitro and in vivo and characterize DV tropism and replication in vivo. * Aim 2 focuses on the early efferent stages of DV infection. We will study gene expression in PBMC during acute DV infection and characterize NK cell responses to DV. * Aim 3 focuses on the adaptive cellular immune response to DV. We will precisely quantify and characterize the DV-specific T cell responses before, during, and after acute DV infection. * Aim 4 focuses on host genetic factors that control innate and adaptive immune responses. We will analyze allele frequencies at specific immune response gene loci in patients with dengue. The long-term objectives of this Project are to identify novel pathophysiologic pathways to which new therapies can be directed and to define immune responses that are protective against DHF in order to guide future vaccine development and testing. This Project addresses core elements of the overall Program Project objectives of improving understanding of DHF pathogenesis to reduce DV-related morbidity and mortality.